Fig. 2.

Phosphodiesterase regulation of cyclic nucleotides within cardiomyocytes. Phosphodiesterases (PDEs) catalyse the hydrolysis and inactivation of cyclic adenosine-3′,5′-monophosphate (cAMP) and cyclic guanosine-3′,5′-monophosphate (cGMP) forming adenosine monophosphate (AMP) and guanosine monophosphate (GMP), respectively. PDEs 1, 2, 3, 4, 5 and 9 are the principal regulators of cAMP and cGMP signalling in cardiomyocytes. PDE1 is calcium/calmodulin (Ca²⁺/CaM)-dependent and hydrolyses cAMP and cGMP. PDE2 is stimulated by cGMP binding to its GAF-B domain. PDE2 degrades cAMP and cGMP, and there is evidence that PDE2 hydrolyses both the natriuretic peptide (NP) and the nitric oxide (NO) pools of cGMP. PDE3 is a dual esterase but is inhibited by cGMP, and PDE4 is cAMP-selective. PDE5 is stimulated by cGMP binding to its GAF-A domain and largely hydrolyses NO/cGMP. PDE9 metabolises NP/cGMP. Abbreviations: AC, adenylyl cyclase; ANP, atrial natriuretic peptide; ATP, adenosine-5′-triphosphate; β-AR, beta-adrenergic receptor; BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide; GAF, cGMP-stimulated PDE, Anabaena AC and Fhla transcription factor; GC, guanylyl cyclase; GTP, guanosine-5′-triphosphate; NA, noradrenaline